The Synthesis Core provides vital enabling technology for the Cystic Fibrosis Research and Translational Core Center. The Synthesis Core (Core D) has all of the equipment required for this effort and Prof. Kurth, the director of the Synthesis Core, has broad experience managing and implementing this equipment in targeted and library small molecule synthesis. The Synthesis Core interacts with Projects in the research base, providing three levels of service. Level I - the highest level of Synthesis Core service - constitutes concentrated involvement by the Synthesis Core in lead optimization and exploration of structure-activity relationships (SAR) by exhaustive synthesis. We anticipate that this level of involvement will continue for AF508-CFTR correctors / potentiators as well as for CaCC/TMEM16A activators. Depending on High- Throughput Screening (HTS) Core (Core A) discovery progress as well as the importance of focused chemistry in meeting Program goals, this level of involvement may also be warranted for other Projects. Level ll - the second level of Synthesis Core involvement - involves the resynthesis of lead compounds, provision of medicinal chemistry advice, and SAR analysis. Many Projects will benefit from this level of Synthesis Core service. Level 111 - the third level of service - requires minimal Synthesis Core effort and consists of providing compounds that have already been synthesized for Project studies as well as providing advice on the medicinal chemistry of active compounds. While individual Project needs will drive most of the Synthesis Core's activities, the Core will also interact with Cores A/B/C/E - primarily in providing any individual compounds needed for their work. The Synthesis Core will interact closely with the HTS Core to verify the identity of hits and validate hit activity by hit re-synthesis and spectroscopic characterization. All lead compounds supplied by the Synthesis Core for Project and Core activities will be highly purified (generally at -95%).